Stribild

"The combinations of anti-HIV drugs recommended for pregnant women do not appear in general to increase their children's risk for language delay, according to a study from a National Institutes of Health research network.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Pharmacodynamics

Effects on Electrocardiogram

Thorough QT studies have been
conducted for elvitegravir and cobicistat. The effect of the other two
components, tenofovir and emtricitabine, or the combination regimen STRIBILD on
the QT interval is not known.

The effect of multiple doses of
elvitegravir 125 and 250 mg (0.83 and 1.67 times the dose in STRIBILD)
(coadministered with 100 mg RTV to boost the blood levels of elvitegravir) on
QTc interval was evaluated in a randomized, placebo-and active-controlled
(moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects.
In a study with demonstrated ability to detect small effects, the upper bound
of the one-sided 95% confidence interval for the largest placebo adjusted,
baseline-corrected QTc based on Fridericia's correction method (QTcF) was below
10 msec. In this study, there was no clinically relevant prolongation of the
QTc interval.

The effect of a single dose of
cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in STRIBILD) on QTc
interval was evaluated in a randomized, placebo-and active-controlled
(moxifloxacin 400 mg) four-period crossover thorough QT study in 48 healthy
subjects. In a study with demonstrated ability to detect small effects, the
upper bound of the one-sided 95% confidence interval for the largest placebo
adjusted, baseline-corrected QTc based on individual correction method (QTc)
was below 10 msec, the threshold for regulatory concern. Prolongation of the PR
interval was noted in subjects receiving cobicistat in the same study. The
maximum mean (95% upper confidence bound) difference in PR from placebo after
baseline-correction was 9.5 (12.1) msec for 250 mg dose and 20.2 (22.8) for 400
mg dose cobicistat. Because the 150 mg cobicistat dose used in the STRIBILD
fixed-dose combination tablet is lower than the lowest dose studied in
the thorough QT study, it is unlikely that treatment with STRIBILD will result
in clinically relevant PR prolongation.

Effect of Food on Oral
Absorption

Relative to fasting conditions,
the administration of single dose STRIBILD with a light meal (~373 kcal, 20%
fat) increased the mean systemic exposure of elvitegravir and tenofovir by 34%
and 24%, respectively. The alterations in mean systemic exposures of cobicistat
and emtricitabine were not clinically significant.

Relative to fasting conditions,
the administration of single dose STRIBILD with a high fat meal (~ 800 kcal,
50% fat) increased the mean systemic exposure of elvitegravir and tenofovir by
87% and 23%, respectively. The alterations in mean systemic exposures of
cobicistat and emtricitabine were not clinically significant.

STRIBILD should be taken with
food.

Distribution

Elvitegravir: Elvitegravir is 98-99% bound to
human plasma proteins and binding is independent of drug concentration over the
range of 1 ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio
was 0.73.

Cobicistat: Cobicistat is 97-98% bound to human
plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.

Emtricitabine:In vitro binding of emtricitabine
to human plasma proteins is less than 4% and is independent of drug
concentration over the range of 0.02–200 micrograms per mL.

Tenofovir Disoproxil Fumarate:In vitro binding of
tenofovir to human plasma proteins is less than 0.7% and is independent of
concentration over the range of 0.01–25 micrograms per mL.

Metabolism

Cobicistat: Cobicistat is metabolized by CYP3A and
to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

Emtricitabine and tenofovir are not significantly
metabolized.

Elimination

Elvitegravir: The median terminal plasma half-life
of elvitegravir following administration of STRIBILD is approximately 12.9
hours. After single dose administration of [14C] elvitegravir
(coadministered with 100 mg RTV), 94.8% and 6.7% of the administered dose was
excreted in feces and urine, respectively.

Cobicistat: The median terminal plasma half-life of
cobicistat following administration of STRIBILD is approximately 3.5 hours.
With single dose administration of [14C] cobicistat after multiple
dosing of cobicistat for six days, 86.2% and 8.2% of the administered dose was
excreted in feces and urine, respectively.

Emtricitabine and tenofovir are primarily excreted in the
urine by a combination of glomerular filtration and active tubular secretion.

Special Populations

Patients with Renal Impairment

Elvitegravir and cobicistat: A study of the
pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy
subjects and subjects with severe renal impairment (estimated creatinine
clearance less than 30 mL per minute). No clinically relevant differences in
elvitegravir or cobicistat pharmacokinetics were observed between healthy
subjects and subjects with severe renal impairment.

Emtricitabine and Tenofovir Disoproxil Fumarate: The
pharmacokinetics of emtricitabine and tenofovir are altered in subjects with
estimated creatinine clearance below 50 mL per minute or with end stage renal
disease requiring dialysis [see WARNINGS AND
PRECAUTIONS and Use In Specific Populations].

Patients with Hepatic Impairment

Elvitegravir and cobicistat: A study of the
pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy
subjects and subjects with moderate hepatic impairment. No clinically relevant
differences in elvitegravir or cobicistat pharmacokinetics were observed
between subjects with moderate hepatic impairment (Child-Pugh Class B) and
healthy subjects. No dosage adjustment of elvitegravir or cobicistat is
necessary for patients with mild to moderate hepatic impairment. The effect of
severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of
elvitegravir or cobicistat has not been studied [see Use in Specific
Populations].

Emtricitabine: The pharmacokinetics of
emtricitabine has not been studied in subjects with hepatic impairment;
however, emtricitabine is not significantly metabolized by liver enzymes, so
the impact of liver impairment should be limited.

Tenofovir Disoproxil Fumarate: The
pharmacokinetics of tenofovir following a 300 mg dose of VIREAD has been
studied in healthy subjects with moderate to severe hepatic impairment. No
clinically relevant differences in tenofovir pharmacokinetics were observed
between subjects with hepatic impairment and healthy subjects.

Cobicistat: There were insufficient
pharmacokinetic data in the clinical trials to determine the effect of
hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.

Emtricitabine and Tenofovir: Pharmacokinetics of
emtricitabine and tenofovir DF have not been fully evaluated in subjects
coinfected with hepatitis B and/or C virus.

Race

Elvitegravir: Population pharmacokinetic analysis
of elvitegravir in HIV-1 infected subjects indicated that race had no
clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.

Cobicistat: Population pharmacokinetics analysis
of cobicistat in HIV-1 infected subjects indicated that race had no clinically
relevant effect on the exposure of COBI.

Emtricitabine: No pharmacokinetic differences due
to race have been identified following the administration of EMTRIVA.

Tenofovir Disoproxil Fumarate: There were
insufficient numbers from racial and ethnic groups other than Caucasian to
adequately determine potential pharmacokinetic differences among these
populations following the administration of VIREAD.

Gender

No clinically relevant pharmacokinetic differences have
been observed between men and women for cobicistat-boosted elvitegravir,
emtricitabine and tenofovir DF.

Pediatric Patients

Emtricitabine has been studied in pediatric subjects from
3 months to 17 years of age. Tenofovir DF has been studied in pediatric
subjects from 2 years to less than 18 years of age. The pharmacokinetics of
elvitegravir or cobicistat in pediatric subjects have not been established [seeUse in Specific Populations].

Geriatric Patients

Pharmacokinetics of elvitegravir, cobicistat,
emtricitabine and tenofovir have not been fully evaluated in elderly (65 years
of age and older) patients [see Use In Specific Populations].

Assessment of Drug Interactions

The drug-drug interaction studies described in Tables 8
and 9 were conducted with STRIBILD, elvitegravir (coadministered with
cobicistat or RTV), or cobicistat administered alone.

As STRIBILD is indicated for use as a complete regimen
for the treatment of HIV-1 infection and should not be administered with other
antiretroviral medications, information regarding drug-drug interactions with
other antiretrovirals agents is not provided [see
WARNINGS AND PRECAUTIONS].

The effects of coadministered drugs on the exposure of
elvitegravir are shown in Table 8. The effects of elvitegravir or cobicistat on
the exposure of coadministered drugs are shown in Table 9. For information
regarding clinical recommendations, see DRUG INTERACTIONS.

Table 8 : Drug Interactions: Changes in
Pharmacokinetic Parameters for Elvitegravir in the Presence of the
Coadministered Druga

Microbiology

Mechanism of Action

Elvitegravir: Elvitegravir inhibits the
strand transfer activity of HIV-1 integrase (integrase strand transfer
inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral
replication. Inhibition of integrase prevents the integration of HIV-1 DNA into
hostgenomic DNA, blocking the formation of the HIV-1 provirus and propagation
of the viral infection. Elvitegravir does not inhibit human topoisomerases I or
II.

Cobicistat: Cobicistat is a
selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A
subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the
systemic exposure of CYP3A substrates, such as elvitegravir, where
bioavailability is limited and half-life is shortened by CYP3A-dependent
metabolism.

Emtricitabine: Emtricitabine, a
synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes
to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits
the activity of the HIV-1 RT by competing with the natural substrate
deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA
which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA
polymerases α, β, ε, and mitochondrial DNA polymerase γ.

Antiviral Activity in Cell Culture

Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir
DF: The triple combination of elvitegravir, emtricitabine, and tenofovir
was not antagonistic in cell culture combination antiviral activity assays and
was not affected by the addition of cobicistat.

Emtricitabine and Tenofovir DF: HIV-1 isolates
with reduced susceptibility to emtricitabine or tenofovir have been selected in
cell culture. Reduced susceptibility to emtricitabine was associated with
M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir
expressed a K65R substitution in HIV-1 RT and showed a 2–4 fold reduction in
susceptibility to tenofovir.

Emtricitabine and Tenofovir DF: HIV-1 isolates with reduced susceptibility to
emtricitabine or tenofovir have been selected in subjects experiencing
virologic failure in clinical trials. Genotypic analysis of these isolates
identified the M184V/I and K65R amino acid substitutions in the viral RT, respectively.

Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir
DF: In clinical trials of HIV-1infected subjects with no antiretroviral
treatment history [Studies 102 and 103, see Clinical Studies], by Week
144, the development of one or more primary substitutions associated with
resistance to elvitegravir, emtricitabine, and/or tenofovir was observed in
viruses from 51% (18/35) of the STRIBILD-treatment failure subjects with
evaluable genotypic resistance data who received at least 8 weeks of STRIBILD
and had HIV-1 RNA greater than or equal to 400 copies per mL at confirmed
virologic failure, the end of each study year, or the time of early study drug
discontinuation. The most common substitutions that emerged were M184V/I (N=17)
in HIV-1 RT and the primary elvitegravir resistance-associated substitutions,
E92Q (N=9), N155H (N=5), Q148R (N=3), T66I (N=2), and T97A (N=1) in integrase;
K65R in RT was also detected (N=5). In virus isolates harboring the observed
primary elvitegravir resistance substitutions, additional substitutions in
integrase were detected including H51Y, L68I/V, G70R, I73V, G140C, S153A,
E157Q, and G163R. The virus in all subjects with evaluable data for RT and IN
and whose virus developed integrase substitutions associated with elvitegravir
resistance (N=14) also developed the M184I/V RT substitutions, and had reduced
susceptibility to both elvitegravir and emtricitabine. In phenotypic analyses,
HIV-1 isolates expressing M184V/I RT substitutions showed reduced
susceptibility to emtricitabine (42-to greater than 152-fold); those expressing
the primary elvitegravir resistance-associated integrase substitutions showed
reduced susceptibility to elvitegravir (4-to greater than 198-fold); and those
expressing the K65R RT substitution showed reduced susceptibility to tenofovir
(0.8-to 1.6-fold), compared to wild-type reference HIV-1.

There was an insufficient number of virologic failures
with evaluable data (N=1) in clinical trials of virologically-suppressed
HIV-1-infected subjects with no history of virologic failure [Studies 115 and
121, see Clinical Studies] to draw conclusions about the development of
resistance.

Cross Resistance

STRIBILD-treatment failure subject isolates exhibited
varying degrees of cross resistance within the INSTI and NRTI drug classes
depending on the specific substitutions observed. These isolates remained
susceptible to all NNRTIs and protease inhibitors.

Elvitegravir: Cross-resistance has been observed
among INSTIs. Elvitegravirresistant viruses showed varying degrees of
cross-resistance in cell culture to raltegravir depending on the type and
number of substitutions in HIV-1 integrase. Of the primary elvitegravir resistance-associated
substitutions tested (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), all
but three (T66I, E92G, and S147G) conferred greater than 1.5-fold reduced
susceptibility to raltegravir (above the biological cutoff for raltegravir)
when introduced individually into a wild-type virus by site-directed
mutagenesis. Of the primary raltegravir resistance-associated substitutions
(Y143C/H/R, Q148H/K/R, and N155H), all but Y143C/H conferred greater than
2.5-fold reductions in susceptibility to elvitegravir (above the biological
cutoff for elvitegravir).

Emtricitabine: Cross-resistance has been observed
among NRTIs. Emtricitabineresistant isolates harboring an M184V/I substitution
in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the
K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir,
demonstrated reduced susceptibility to inhibition by emtricitabine.

Tenofovir DF: Cross-resistance has been observed
among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also
selected in some HIV-1infected patients treated with abacavir or didanosine.
HIV-1 isolates with the K65R substitution also showed reduced susceptibility to
emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may
occur in patients whose virus harbors the K65R substitution. The K70E
substitution selected clinically by tenofovir DF results in reduced
susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and
tenofovir. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of
3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W,
T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to
tenofovir. Subjects whose virus expressed an L74V RT substitution without
zidovudine resistance-associated substitutions (N=8) had reduced response to
tenofovir DF. Limited data are available for patients whose virus expressed a
Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4) in
HIV-1 RT, all of whom had a reduced response in clinical trials.

Clinical Studies

The efficacy of STRIBILD in HIV-1 Infected patients with
no antiretroviral treatment history is based on the analyses of 144-week data
from two randomized, double-blind, active-controlled trials, Study 102 and
Study 103 (N=1408, randomized and dosed). The efficacy of STRIBILD in
virologically-suppressed HIV-1 infected patients without a history of virologic
failure is based on the analyses of 48-week data from two randomized,
open-label, controlled studies, Study 115 and Study 121 (N=867, randomized and
dosed). Patients in all four studies had estimated creatinine clearance greater
than or equal to 70 mL/min at screening.

In HIV-1-Infected Subjects With No Antiretroviral
Treatment History

In Study 102, subjects were randomized in a 1:1 ratio to
receive either STRIBILD (N=348) once daily or ATRIPLA (efavirenz 600
mg/emtricitabine 200 mg/tenofovir DF 300 mg; N=352) once daily. The mean age
was 38 years (range 18-67), 89% were male, 63% were White, 28% were Black, and
2% were Asian. Twenty-four percent of subjects identified as Hispanic/Latino.
The mean baseline plasma HIV-1 RNA was 4.8 log10 copies per mL (range 2.6–6.5).
The mean baseline CD4+ cell count was 386 cells per mm³ (range
3-1348) and 13% had CD4+ cell counts less than 200 cells per mm³.
Thirty-three percent of subjects had baseline viral loads greater than 100,000
copies per mL.

Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLd

5%

7%

8%

9%

Missing Data During Window but on Study Drug

1%

0%

1%

1%

a Week 144 window is between Day 967 and 1050
(inclusive). b. Includes subjects who had ≥ 50 copies/mL in the Week 144
window, subjects who discontinued early due to lack or loss of efficacy,
subjects who discontinued for reasons other than an adverse event, death or
lack or loss of efficacy and at the time of discontinuation had a viral value
of ≥ 50 copies/mL. c Includes patients who discontinued due to adverse event or death
at any time point from Day 1 through the time window if this resulted in no
virologic data on treatment during the specified window. d Includes subjects who discontinued for reasons other than an
adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss
to follow-up, etc.

In Study 102, the mean increase
from baseline in CD4+ cell count at Week 144 was 298 cells per mm³ in
the STRIBILD-treated subjects and 272 cells per mm³ in the ATRIPLA
treated subjects. In Study 103, the mean increase from baseline in CD4+ cell
count at Week 144 was 261 cells per mm³ in the STRIBILD-treated
subjects and 269 cells per mm³ in the ATV + RTV + TRUVADA-treated
subjects.

In Virologically-Suppressed
HIV-1-Infected Subjects with No History of Virologic Failure

In Study 115, subjects had to
be on either their first or second antiretroviral regimen with no history of
virologic failure, with no current or past history of resistance to the
antiretroviral components of STRIBILD and must have been suppressed (HIV-1 RNA
< 50 copies/mL) on a ritonavir-boosted PI in combination with TRUVADA for at
least 6 months prior to screening. Subjects were randomized in a 2:1 ratio to
either switch to STRIBILD (STRIBILD arm, N=293; randomized and dosed) or stay
on their baseline antiretroviral regimen for 48 weeks (PI + RTV + TRUVADA arm,
N=140; randomized and dosed). Subjects had a mean age of 41 years (range
21-76), 86% were male, 80% were White, and 15% were Black. The mean baseline
CD4+ cell count was 610 cells per mm³ (range 74-1919). At screening
subjects were receiving atazanavir (40%), darunavir (40%), lopinavir (17%),
fosamprenavir (3%), or saquinavir ( < 1%) as the PI in their regimen.

In Study 121, subjects had to
be on either their first or second antiretroviral regimen with no history of
virologic failure, with no current or past history of resistance to the
antiretroviral components of STRIBILD and must have been suppressed (HIV-1 RNA
< 50 copies/mL) on a NNRTI in combination with TRUVADA for at least 6 months
prior to screening. Subjects were randomized in a 2:1 ratio to either switch to
STRIBILD (STRIBILD arm, N = 291; randomized and dosed), or stay on their
baseline antiretroviral regimen for 48 weeks (NNRTI +TRUVADA arm, N = 143;
randomized and dosed). Subjects had a mean age of 41 years (range 20-72), 93%
were male, 78% were White, and 17% were Black. The mean baseline CD4+ cell
count was 588 cells per mm³ (range 100-1614). Randomization was
stratified by use of efavirenz in the baseline regimen. At screening
subjects were receiving efavirenz (78%) (predominantly as ATRIPLA [74%]),
nevirapine (17%), rilpivirine (4%) (as COMPLERA [4%]), or etravirine (1%) as
the NNRTI in their regimen.

Virologic outcomes of Study 115 and Study 121 are
presented in Table 11. Five treated subjects were excluded from the efficacy
analysis: in Study 115, three STRIBILD subjects had protocol-prohibited
documented resistance and one PI + RTV + TRUVADA subject was not on a protease
inhibitor-based regimen at screening; in Study 121, one STRIBILD subject had
protocol-prohibited documented resistance.

Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLd

4%

10%

4%

9%

Missing Data During Window but on Study Drug

0%

0%

0%

1%

a Week 48 window is between Day 295 and 378
(inclusive). b Includes subjects who had ≥ 50 copies/mL in the Week 48
window, subjects who discontinued early due to lack or loss of efficacy,
subjects who discontinued for reasons other than an adverse event, death or
lack or loss of efficacy and at the time of discontinuation had a viral value
of ≥ 50 copies/mL. c Includes subjects who discontinued due to adverse event or death
at any time point from Day 1 through the time window if this resulted in no
virologic data on treatment during the specified window. d Includes subjects who discontinued for reasons other than an
adverse event, death or lack or loss of efficacy, eg., withdrew consent, loss
to follow-up, etc.

Last reviewed on RxList: 1/2/2015
This monograph has been modified to include the generic and brand name in many instances.